Blocking AURKA with MK-5108 attenuates renal fibrosis in chronic kidney disease

Abstract

Renal fibrosis, a common feature of chronic kidney disease (CKD), is characterized by excessive deposition of extracellular matrix (ECM) leading to scar formation in the renal parenchyma. Active epithelial-mesenchymal communication (EMC), and the proliferation and activation of fibroblasts are implicated in the causation of renal fibrosis. Aurora-A kinase (AURKA) is a serine/threonine kinase required for the process of mitosis. Dysregulation of AURKA has been demonstrated in the context of various cancers. However, the role of AURKA in CKD-associated fibrosis has not been elucidated. MK-5108, a potent and highly selective AURKA inhibitor, was shown to exhibit anti-cancer activity in recent preclinical and clinical studies. In the present study, we investigated the role of MK-5108 in renal fibrosis employing animal and cell models. In vivo, AURKA was highly expressed in fibrotic kidneys of CKD patients and in mouse kidneys with unilateral ureteral obstruction (UUO). Post treatment with MK-5108 at the 3rd day after UUO remarkably alleviated renal fibrosis, possibly by inhibiting the proliferation and activation of fibroblasts and suppressing the phenotypic transition of renal cells. Moreover, the enhanced inflammatory factors in obstructive kidneys were also repressed. In vitro, MK-5108 treatment inhibited the pro-fibrotic response in renal cells induced by transforming growth factor-β1. Finally, overexpression of AURKA in renal fibroblasts promoted fibrotic response, while silencing AURKA showed anti-fibrotic effect, further confirming the pro-fibrotic role of AURKA. In this study, inhibition of AURKA by MK-5108 markedly attenuated renal fibrosis. MK-5108 is a potential therapeutic agent for treatment of renal fibrosis in CKD.